DuoTrav 40 micrograms/mL + 5 mg/mL eye drops, solution

update to sections 4.6, 4.8 of the smpc in line with ccds

- Update to SPC following transfer of MAH from Alcon to Novartis.

- Minor amendment

- SPC updated following Type II resin change.

 - Section 4.8 updated to include the IMB- HPRA name change.
- Section 6.3 updated to change shelf life from 3 to 2 years

Section 6.4: Updated storage conditions from "This medicinal product does not require any special storage conditions." to "Do not store above 30°C."

MAH address update

4.2     Posology and method of administration

 

Posology

Use in adults, including the elderly population

 

The dose is one drop of DuoTrav in the conjunctival sac of the affected eye(s) once daily, in the morning or evening. It should be administered at the same time each day.

 

If a dose is missed, treatment should be continued with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily.

 

Special Populations

Hepatic and renal impairment

No studies have been conducted with DuoTrav or with timolol 5 mg/ml eye drops in patients with hepatic or renal impairment.

 

Travoprost has been studied in patients with mild to severe hepatic impairment and in patients with mild to severe renal impairment (creatinine clearance as low as 14 ml/min). No dose adjustment was necessary in these patients.

Patients with hepatic or renal impairment are unlikely to require dose adjustment with DuoTrav (see section 5.2).

 

Paediatric population

The safety and efficacy of DuoTrav in children and adolescents below the age of 18 years have not been established. No data are available.

 

Method of administration

For ocular use.

The patient should remove the protective overwrap immediately prior to initial use. To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle.

 

Nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions.

 

When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.

 

If more than one topical ophthalmic medicinal product is being used, the medicinal products must be administered at least 5 minutes apart (see section 4.5).

 

When substituting another ophthalmic antiglaucoma medicinal product with DuoTrav, the other medicinal product should be discontinued and DuoTrav should be started the following day.

 

Patients must be instructed to remove soft contact lenses prior to application of DuoTrav and wait 15 minutes after instillation of the dose before reinsertion.

 

4.3       Contraindications

 

Hypersensitivity to the active substances, or to any of the excipients.

Hypersensitivity to other beta‑blockers.

Reactive airway disease including bBronchial asthma, or a history of bronchial asthma or, severe chronic obstructive pulmonary disease.

Sinus bradycardia, sick sinus syndrome, including sino-atrial block, second or third degree atrioventricular block not controlled with pace-maker., overt Overt cardiac failure, or cardiogenic shock.

Severe allergic rhinitis and bronchial hyper reactivity; corneal dystrophies; hypersensitivity to other beta‑blockers.

 

4.4       Special warnings and precautions for use

 

Systemic effects

Like other topically applied ophthalmic medicinal productsagents, travoprost and timolol are absorbed systemically. Due to the beta‑adrenergic active substance component, timolol, the same types of cardiovascular, and pulmonary  and other adverse reactions as seen with systemic beta -adrenergic blocking medicinal products agents may occur. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.

 

Cardiac failure should be adequately controlled before beginning therapy with timolol. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked. Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death in association with cardiac failure, have been reported following administration of timolol maleate. Beta‑adrenergic blocking medicinal products should be administered with caution in patients subject to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) as beta‑adrenergic blocking medicinal products  may mask the signs and symptoms of acute hypoglycaemia. They may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension.

Cardiac disorders

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions.

 

Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.

 

Vascular disorders

Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution.

 

Respiratory disorders:

Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers.

 

DuoTrav should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.

 

Hypoglycaemia/diabetes

Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.

 

Corneal diseases

Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.

 

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.

 

Other beta-blocking agents

The effect on intra-ocular pressure or the known effects of systemic beta‑blockade may be potentiated when timolol is given to the patients already receiving a systemic beta‑blocking agent. The response of these patients should be closely observed. The use of two topical beta‑adrenergic blocking agents is not recommended (see section 4.5).

 

Surgical anaesthesia

Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.

 

Beta-blockers may mask the signs of hyperthyroidism.

 

Skin contact

Prostaglandins and prostaglandin analogues are biologically active substances that may be absorbed through the skin. Women who are pregnant or attempting to become pregnant should exercise appropriate precautions to avoid direct exposure to the contents of the bottle. In the unlikely event of coming in contact with a substantial portion of the contents of the bottle, thoroughly cleanse the exposed area immediately.

 

Anaphylactic reactions

While taking beta adrenergic blocking medicinal products, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.

While taking beta-blockers, patients with history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.

 

Concomitant therapy

Timolol may interact with other medicinal products (see section 4.5).

The effect on intraocular pressure or the known effects of systemic beta‑blockade may be potentiated when DuoTrav is given to patients already receiving an oral beta‑blocking medicinal product .

 

The use of two local beta‑adrenergic blocking medicinal products or two local prostaglandins is not recommended.

 

Ocular effects

Travoprost may gradually change the eye colour by increasing the number of melanosomes (pigment granules) in melanocytes. Before treatment is instituted, patients must be informed of the possibility of a permanent change in eye colour. Unilateral treatment can result in permanent heterochromia. The long‑term effects on the melanocytes and any consequences thereof are currently unknown. The change in iris colour occurs slowly and may not be noticeable for months to years. The change in eye colour has predominantly been seen in patients with mixed coloured irides, i.e., blue‑brown, grey‑brown, yellow‑brown and green‑brown; however, it has also been observed in patients with brown eyes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery in affected eyes, but the entire iris or parts of it may become more brownish. After discontinuation of therapy, no further increase in brown iris pigment has been observed.

 

In controlled clinical trials, periorbital and/or eyelid skin darkening in association with the use of travoprost has been reported.

 

Travoprost may gradually change eyelashes in the treated eye(s); these changes were observed in about half of the patients in clinical trials and include: increased length, thickness, pigmentation, and/or number of lashes. The mechanism of eyelash changes and their long term consequences are currently unknown.

 

Travoprost has been shown to cause slight enlargement of the palpebral fissure in studies in the monkey. However, this effect was not observed during the clinical trials and is considered to be species specific.

 

There is no experience of DuoTrav in inflammatory ocular conditions; nor in neovascular, angle‑closure, narrow‑angle or congenital glaucoma and only limited experience in thyroid eye disease, in open‑angle glaucoma of pseudophakic patients and in pigmentary or pseudoexfoliative glaucoma.

 

Caution is recommended when using DuoTrav in aphakic patients, pseudophakic patients with a torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema.

 

In patients with known predisposing risk factors for iritis/uveitis, DuoTrav can be used with caution.

 

Excipients

DuoTrav contains propylene glycol which may cause skin irritation.

 

DuoTrav contains polyoxyethylene hydrogenated castor oil 40 which may cause skin reactions.

 

Patients must be instructed to remove contact lenses prior to application of DuoTrav and wait 15 minutes after instillation of the dose before reinsertion.

 

4.5     Interaction with other medicinal products and other forms of interaction

 

No specific drug interaction studies have been performed with travoprost or timolol.

There is a potential for additive effects resultsing in hypotension and/or marked bradycardia when ophthalmic beta blockers solution eye drops with timolol are is administered concomitantly with oral calcium channel blockers, guanethidine or beta‑adrenergic blocking agentsmedicinal products, antiarrhythmics (including amiodarone), digitalis glycosides, or parasympathomimetics,guanethidine.

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta‑blockers.

 

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.

 

Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.

 

Beta‑blockers may increase the hypoglycaemic effect of antidiabetic medicinal products. Beta‑blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4).

 

4.6     Fertility, pregnancy and lactation

 

Women of childbearing potential/contraception

DuoTrav must not be used in women who may become pregnant unless adequate contraceptive measures are in place (see section 5.3).

 

Pregnancy

Travoprost has harmful pharmacological effects on pregnancy and/or the foetus/new‑born child.

 

There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary.

 

 

Well controlled epidemiological studies with systemic use of beta‑blockers did not indicate malformative effects, but some pharmacological effects such as bradycardia have been observed in foetuses or neonates. Data on a limited number of exposed pregnancies indicate no adverse effects of timolol in eye drops on pregnancy or on the health of the foetus/newborn child but bradycardia and arrhythmia have been reported in one case in the foetus of a woman treated with timolol eye drops. To date, no other relevant epidemiological data are available.

 

Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If DuoTrav is administered until delivery, the neonate should be carefully monitored during the first days of life.

 

DuoTrav should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2.

 

Breastfeeding

It is unknown whether travoprost from eye drops is excreted in human breast milk. Animal studies have shown excretion of travoprost and metabolites in breast milk. Timolol is excreted in breast milk. However, at therapeutic doses of timolol in eye drops the calculated dose of timolol for the infant would be too low to produce clinical beta‑blockade. Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption, see section 4.2.

The use of DuoTrav by breast‑feeding women is not recommended.

 

Fertility

There are no data on the effects of DuoTrav on human fertility. Animal studies showed no effect of travoprost or timolol on fertility at doses more than 250 times the maximum recommended human ocular dose.

4.8     Undesirable effects

 

In clinical studies involving 938 patients, DuoTrav (benzalkonium chloride-preserved) was administered once‑daily. The most frequently reported treatment‑related adverse reaction was ocular hyperaemia (15.0%). Almost all patients (96%) who experienced ocular hyperaemia did not discontinue therapy as a result of this reaction.

 

The following adverse reactions listed in the table below were observed in clinical studies or with post‑marketing experience.  They are ranked according to system organ class and classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in decreasing order of seriousness.

 

DuoTrav (benzalkonium chloride-preserved)

 

System Organ Class	Frequency	Adverse Reactions
Psychiatric disorders	Common	nervousness.
	Not known	depression.
Nervous system disorders	Common	dizziness, headache.
	Not known	cerebrovascular accident, syncope, paraesthesia.
Eye disorders	Very common	ocular discomfort, ocular hyperaemia
	Common	punctate keratitis, anterior chamber inflammation, eye pain, photophobia, eye swelling, conjunctival haemorrhage, visual acuity reduced, visual disturbance, vision blurred, dry eye, eye pruritus, conjunctivitis, lacrimation increased, erythema of eyelid, blepharitis, asthenopia, growth of eyelashes.
	Uncommon	corneal erosion, keratitis, eye allergy, conjunctival oedema, eyelid oedema.
	Rare	iritis.
	Not known	macular oedema, eyelid ptosis, corneal disorder.
Cardiac disorders	Common Uncommon Not known	heart rate irregular, heart rate decreased. arrhythmia. cardiac failure, tachycardia.
Vascular disorders	Common	blood pressure increased, blood pressure decreased.
Respiratory, thoracic and mediastinal disorders	Common	bronchospasm.
	Uncommon	dyspnoea, cough, oropharyngeal pain, throat irritation, nasal discomfort, postnasal drip.
	Not known	asthma.
Hepatobiliary disorders	Uncommon	alanine aminotransferase increased, aspartate aminotransferase increased.
Skin and subcutaneous tissue disorders	Common	urticaria, skin hyperpigmentation (periocular).
	Uncommon	dermatitis contact.
	Rare	alopecia.
	Not known	rash.
Musculoskeletal and connective tissue disorders	Common	pain in extremity.
Renal and urinary disorders	Uncommon	chromaturia.
General disorders and administration site conditions	Uncommon	thirst.
	Not known	chest pain.

 

In 3 clinical trials involved in the development of DuoTrav (polyquaternium‑1‑preserved), 372 patients/subjects were exposed for up to 12 months. The most frequently reported treatment‑related undesirable effect with DuoTrav (polyquaternium‑1‑preserved) was hyperaemia of the eye (11.8%), which included ocular or conjunctival hyperaemia. The majority of patients (91%) who experienced hyperaemia of the eye did not discontinue therapy as a result of this reaction.

 

The following adverse reactions listed in the table below were observed in the clinical studies.

 

DuoTrav (polyquaternium-1-preserved)

 

System Organ Classification	Frequency	Adverse Reactions
Immune system disorders	Uncommon	hypersensitivity
Nervous system disorders	Uncommon	Headache
Eye disorders	Common	eye pain, ocular discomfort, dry eye, eye pruritus, ocular hyperaemia
	Uncommon	punctate keratitis, iritis, photophobia, vision blurred, conjunctivitis,meibomianitis, eyelid margin crusting, asthenopia, lacrimation increased, growth of eye lashes
Cardiac disorders	Uncommon	Bradycardia
Vascular disorders	Uncommon	hypotension
Skin and subcutaneous tissue disorders	Uncommon	skin discolouration, hair growth abnormal
General disorders and administration site conditions	Uncommon	fatigue
Investigations	Uncommon	heart rate decreased

 

Additional adverse reactions that have been seen with one of the active substances and may potentially occur with DuoTrav:

 

Travoprost

 

Eye disorders uveitis, conjunctival disorder, conjunctival follicles,  iris hyperpigmentation.

 

Skin and subcutaneous tissue disorders skin exfoliation.

 

Timolol

 

Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Additional listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration.  To reduce the systemic absorption, see 4.2.

 

Immune system disorders:

Systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylaxis.

 

Metabolism and nutrition disorders:

 hHypoglycaemia.

 

Psychiatric disorders:

Insomnia, nightmares, memory loss.

 

Nervous system disorders

cCerebral ischaemia, increases in signs and symptoms of myasthenia gravis.

 

Eye disorders: diplopia.

signs and symptoms of ocular irritation (e.g. burning, stinging, itching, tearing, redness), choroidal detachment following filtration surgery (see 4.4 Special warnings and special precautions for use),

decreased corneal sensitivity, diplopia.

 

Cardiac disorders:

 cardiac arrest, atrioventricular block, palpitations Chest pain, palpitations, oedema, congestive heart failure, atrioventricular block, cardiac arrest.

.

Vascular disorders:

Raynaud's phenomenon, cold hands and feet.

 

Respiratory, thoracic and mediastinal disorders:

 respiratory failure,Bronchospasm (predominantly in patients with pre-existing bronchospastic disease).

.

 

Gastrointestinal disorders:

 diarrhoea, nausea. Dysgeusia, nausea, dyspepsia, diarrhoea, dry mouth, abdominal pain, vomiting.

 

Skin and subcutaneous tissue disorders:

Psoriasiform rash or exacerbation of psoriasis.

 

Musculoskeletal and connective tissue disorders:

Myalgia.

 

Reproductive system and breast disorders:

Sexual dysfunction, decreased libido.

 

 

General disorders and administration site conditions:

 aAsthenia.

10.     DATE OF REVISION OF THE TEXT

 

 

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu

17 February 2012

In Section 2, Qualitative and quantitative composition, excipient has changed from benzalkonium chloride to poyquaternium-1 and propylene glycol.

In Section 4.4, Special warnings and precautions for use, warnings related to benzalkonium chloride are replaced by warnings related to polyquaternuim-1 and propylene glycol.

In Section 4.8, Undesirable effects, side effects related to polyquaternuim-1 and propylene glycol are added.

In Section 5.1, Pharmacodynamic properties, the following statement is added – ‘In a 6-week, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 24 to 26 mmHg, the mean IOP-lowering effect of DuoTrav (polyquaternium-1-preserved) dosed once-daily in the morning was 8 mmHg and equivalent to that of DuoTrav (benzalkonium chloride-preserved).’

In Section 5.2, Pharmacokinetic properties, information related to polyquaternuim-1 and propylene glycol is added.

In Section 5.3, Pre-clinical safety data, the following statement is added – ‘DuoTrav preserved with polyquaternium-1 induced minimal ocular surface toxicity, compared to eye drops preserved with benzalkonium chloride, on cultured human corneal cells and following topical ocular administration in rabbits.’

In Section 6.1, List of excipients, the list has been updated.

In Section 10, Date of revision of the text, the date of revision is updated.

• In Section 2 (Qualitative and quantitative composition), ‘1 ml’ is changed to ‘Each ml’, ‘benzalkonium chloride 0.15mg, polyoxyethylene hydrogenated castor oil 40 (HC0 40) 5 mg (see section 4.4)’ changed to ‘Each ml of solution contains 0.15ml of benzalkonium chloride and 5mg polyoxyethylene hydrogenated castor oil 40’
• In Section 3 (Pharmaceutical form), ‘drops’ is replaced with ‘drop’
• In Section 4.1 (Therapeutic indications), ‘in patients’ is replaced with ‘in adult patients’
• In Section 4.2 (Posology and method of administration)-
-Sub-section ‘Posology’ is added, ‘elderly’ is replaced with ‘elderly population’.
-Information on nasolacrimal occlusion and usage of more than on topical ophthalmic product is moved to the sub-section ‘method of administration’. Also, information on contact lenses and substitution of a different antiglaucoma medicinal product with DuoTrav has been included in this sub-section.
-Information on hepatic and renal impairment has been moved to the sub-section ‘special populations’
• In Section 4.3 (Contraindications), ‘travoprost, timolol’ are replaced with ‘the active substances’
• In Section 4.4 (Special warnings and precautions for use),
-‘ophthalmic agents’ replaced with ‘ophthalmic medicinal products’
-‘beta adrenergic component’ replaced with ‘beta adrenergic active substance’
-‘beta adrenergic blocking agents’ replaced with ‘beta adrenergic blocking medicinal products’
-‘biologically active materials’ replaced with ‘biologically active substances’
-‘beta blocking agent’ replaced with ‘beta blocking medicinal product’
-‘irritation’ replaced with ‘eye irritation’
-‘ Patients must be instructed to remove contact lenses prior to application of DuoTrav and wait 15 minutes after instillation of the dose before reinsertion’ is removed
• In Section 4.5 (Interaction with other medicinal products and other forms of interaction),
-‘beta blocking agent’ replaced with ‘beta blocking medicinal product’
-‘ antidiabetic agents’ replaced with ‘antidiabetic medicinal products’
• Section 4.6 (Pregnancy and lactation) is changed to ‘Fertility, pregnancy and lactation’; and information on fertility is included.
• In Section 4.7 (Effects on ability to drive and use machines), ‘machinery’ replaced with ‘machines’
• In Section 4.8 (Undesirable Effects), ‘undesirable effects’ replaced with ‘adverse reactions’;  new system organ classes ‘Psychiatric disorders, hepatobiliary disorders’ are included, and the tabnle structure is reorganized.
• In section 4.9 (Overdose), ‘A topical overdose with travoprost is not likely to occur or to be associated with toxicity. The most common symptoms of a systemic timolol overdose are bradycardia, hypotension, bronchospasm and heart failure’ is added.
• In Section 5.1(Pharmacodynamic properties), ‘beta blocking agents timolol, combinations’ is removed
• In Section 5.2 (Pharmacokinetic properties), ‘Metabolism’ replaced with ‘Biotransformation’ and ‘Excretion’ replaced with ‘Elimination’
• In Section 6.1 (List of Excipients), ‘Mannitol’ replaced with ‘Mannitol (E421)’
• In Section 6.5 (Nature and contents of container), ‘Cartons containing’ replaced with ‘Pack sizes of’.